Qi Pei, Volkin David B, Zhao Hui, Nedved Michael L, Hughes Robert, Bass Ryan, Yi Sun C, Panek Mark E, Wang Dana, Dalmonte Paul, Bond Michael D
Pharmaceutical Development Department, Centocor R&D, Inc., 145 King of Prussia Road, Radnor, Pennsylvania 19087, USA.
J Pharm Sci. 2009 Sep;98(9):3117-30. doi: 10.1002/jps.21617.
The photodegradation of a human IgG1 monoclonal antibody has been examined in a high concentration (100 mg/mL) liquid formulation. It was observed that a yellowish color is generated when the formulation is exposed to intense and prolonged light exposure, and this discoloration occurs along with a loss in bioactivity. Extensive analytical characterization was performed to determine light induced degradation pathways that occur during exposure to intense light of ICH photodegradation conditions. It has been shown that the monoclonal antibody undergoes a combination of physical and chemical reactions under these conditions, including covalent aggregate formation, fragmentation at the hinge region, oxidation of Trp, His, and Met residues, and deamidation of Asn residues. Oxidation of Trp 94 and deamidation of Asn 93, located in the light chain CDR region, correlates with loss of bioactivity under these conditions. A series of formulation experiments were performed to elucidate the impact of the extent of light exposure, oxygen, protein concentration, and solution pH on the photostability of the formulation. Results demonstrated that photodegradation of the IgG, after intensive light exposure, can be prevented by proper secondary packaging. In addition, it is also shown that a high concentration, liquid dosage form of a human monoclonal antibody is stable upon exposure to the ambient light conditions encountered during routine manufacturing, long-term storage, and administration with proper design of formulation conditions, the primary container as well as the secondary package.
已在高浓度（100 mg/mL）液体制剂中研究了人IgG1单克隆抗体的光降解情况。观察到，当制剂暴露于强烈且长时间的光照下时会产生淡黄色，并且这种变色伴随着生物活性的丧失。进行了广泛的分析表征，以确定在ICH光降解条件下暴露于强光期间发生的光诱导降解途径。结果表明，在这些条件下，单克隆抗体经历了物理和化学反应的组合，包括共价聚集体形成、铰链区断裂、色氨酸、组氨酸和甲硫氨酸残基的氧化以及天冬酰胺残基的脱酰胺作用。位于轻链CDR区域的色氨酸94的氧化和天冬酰胺93的脱酰胺作用与这些条件下生物活性的丧失相关。进行了一系列制剂实验，以阐明光照程度、氧气、蛋白质浓度和溶液pH对制剂光稳定性的影响。结果表明，经过适当的二次包装，可以防止IgG在强光照射后的光降解。此外，研究还表明，通过适当设计制剂条件、一级容器以及二级包装，人单克隆抗体的高浓度液体制剂在常规生产、长期储存和给药过程中遇到的环境光照条件下是稳定的。
